1. Field of the Invention
The present invention is broadly directed to a method for inhibiting pulmonary vascular permeability, bronchial smooth muscle contractility, and airway hyperactivity. The present invention is particularly directed to the use of a particular class of isozyme selective Protein Kinase C (PKC) inhibitors for treating asthma and the syndromes associated therewith.
2. Description of Related Art
Asthma is a disease of airways that is characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli. Three percent of the population of the United States suffers from the disease. Similar figures have been reported from other countries. Bronchial asthma occurs at all ages but predominantly in early life. About one-half of the cases develop before age 10 and another third occur before age 40. In childhood, there is a 2:1 male/female preponderance which equalizes by age 30. The common denominator underlying the asthmatic diathesis is a nonspecific hyperirritability of the tracheobronchial tree.
We believe protein kinase C (PKC) is involved in the signal transduction pathways that mediate the disease conditions associated with asthma, e.g., airway hyperactivity, bronchial smooth muscle contraction, and extravasation of fluid from the vascular into the interstitial space of the lung. Inflammatory responses that accompany the asthmatic attack activate PKC in bronchial smooth muscle cells. Activation of PKC stimulates smooth muscle contraction including the smooth muscles of the respiratory tract (Itoh et al., 1993, J. Physiol. 397: 401; Peiper et al., 1996, Pflugers Arch. Eur. J. Physiol. 432: R47).
Mediators of inflammatory responses are thought to activate PKC by binding to their cognate receptors and activating a variety of signaling pathways which leads to productions of intracellular activators of PKC, e.g., diacylglycerol (Blobe et al., 1996, Cancer Surveys 27: 213). PKC dependent contraction might be mediated by enhancing the phosphorylation of myosin light chain kinase either due to a direct phosphorylation process (Itoh et al., 1993, J Physiol. 397: 401) or to a decrease in the activity of myosin light chain kinase phosphatases (Cohen, 1989, Proc. R. Soc. Lond. Biol. 234: 115).
Extravasation of fluid may be mediated directly via PKC activation either by enhanced transcytosis, retraction of endothelial cells, or passage through the intercellular junctions (Lum et al., 1996, Can. J Physiol. Pharmaco.l 74: 787). PKC-.beta. has been implicated as the PKC isoform responsible for increasing endothelial cell permeability (Nagpala et al., 1995, J. Cell. Physiol. 166: 249).
PKC inhibitors have been demonstrated to reduce smooth muscle contraction in diabetic rodents. In diabetes, PKC is chronically activated by the intracellular accumulation of diacylglycerol (Craven et al., 1989, J. Clin. Invest. 83:1667 and Craven, 1990, Diabetes 39: 667). A prolongation of the mean retinal circulation time is associated with the PKC activation and is thought to be due to enhanced smooth muscle contractile state which leads to an increase in vascular resistance (Ishii et al., 1996, Science 272: 728). Treatment of diabetic rodents with a PKC-.beta. selective inhibitor normalized the prolonged retinal circulation time (Ishii et al., 1996).
Presently, no effective therapy is available for asthma. Elimination of the causative agent(s) from the environment of an allergic asthmatic is the most successful means available of treating this condition. Desensitization or immunotherapy with extracts of the suspected allergens also has enjoyed widespread favor, but controlled studies are limited and have not proved it to be highly effective.
The drugs thus far used in the treatment of asthma may be broken down into five major categories: methylxanthines, beta-adrenergic agonists, glucocorticoids, chromones, and anticholinergics. Because there are few controlled trials that have conclusively demonstrated the superiority of one regimen over the other, specific recommendations for therapy are difficult to make.
As one can appreciate, the presently available treatments for asthma are not completely effective. There remains a need in the art to develop additional therapies for asthma and the syndromes associated therewith.